The chlorinated dibenzo-p-dioxins are among the most toxic synthetic compounds known. Of this class of compounds, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic isomer. The overall goal of the research described in this application is to investigate the biochemical and molecular mechanisms by which TCDD exerts its toxic effects in mammals. Altered lipid metabolism in humans and animals exposed to TCDD has been reported. Proposed studies will determine whether the hyperlipidemia observed in guinea pigs following TCDD treatment is due to increased synthesis and/or decreased catabolism of lipoproteins and will identify the tissue(s) responsible. Various radioisotope techniques and compounds known to alter lipoprotein secretion will be utilized. Studies utilizing techniques in vivo and in vitro will examine the role of fatty acid mobilization from adipose tissue and altered hepatic fatty acid metabolism in this TCDD-induced hyperlipidemia. Alterations in serum insulin and glucagon levels will be determined and the biochemical pathways controlling fatty acid, cholesterol and triglyceride synthesis will be examined. The cytosolic receptor for TCDD in guinea pigs, rats, mice and hamsters will be studied to determine if different properties of these receptors may account for the marked variability in species susceptibility to TCDD-induced toxicity. The concentrations of cytosolic receptor will be determined using a hydroxylapatite technique. The receptors' affinity for TCDD and binding specificity will be examined. The TCDD-receptor complex will be examined for differences in size and molecular weight by various chromatographic and density gradient methods. The ability of this complex to translocate to the nucleus will be examined in vivo and in vitro. The ability of TCDD to alter particular enzymatic systems in tissues of the hamster will also be examined.